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Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model

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World Journal of Gastroenterology 2024年第5期30卷 471-484页

作者： Hui Hua Qian-Qian Zhao Miriam Nkesichi Kalagbor Guo-Zhi Yu Man Liu Zheng-Rui Bian Bei-Bei Zhang Qian Yu Yin-Hai Xu Ren-Xian Tang Kui-Yang Zheng Chao Yan Jiangsu key laboratory of immunity and Metabolism Department of Pathogenic Biology and ImmunologyNational Demonstration Center for Experimental Basic Medical Science EducationLaboratory of Infection and ImmunityXuzhou Medical UniversityXuzhou 221004Jiangsu ProvinceChina department of laboratory Medicine The Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221002Jiangsu ProvinceChina

BACKGROUND Primary sclerosing cholangitis(PSC)is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment *** adeno-associated virus(rAAV)provides a promising platform for gene therapy on such kinds of diseases.A microRNA(miRNA)let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been *** To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8(rAAV8)on a xenobiotic-induced mouse model of sclerosing *** A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine(DDC)feeding for 2 wk or 6 wk.A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC *** sacrifice,the liver and the serum were collected from each *** hepatobiliary injuries,hepatic inflammation and fibrosis were *** targets of let-7a-5p and downstream molecule NF-κB were detected using Western *** rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 *** reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers,and prevent the proliferation of cholangiocytes and biliary ***,inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1,which consequently inhibit of NF-κB-mediated hepatic *** Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis,which provides a possible clinical translation of PSC of human.

关键词： Primary sclerosing cholangitis Recombinant adeno-associated virus 8 Let-7a-5p Therapeutic effects Inflammation

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Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

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Acta Pharmaceutica Sinica B 2024年第1期14卷 87-109页

作者： Letian Song Shenghua Gao Bing Ye Mianling Yang Yusen Cheng Dongwei Kang Fan Yi Jin-Peng Sun Luis Menéndez-Arias Johan Neyts Xinyong Liu Peng Zhan department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Shenzhen Research Institute of shandong University Shenzhen 518057China The key laboratory of infection and immunity of shandong province Department of PharmacologySchool of Basic Medical SciencesShandong UniversityJinan 250012China key laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Centro de Biologı´a Molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientı´ficas&Autonomous University of Madrid) Madrid 28049Spain KU Leuven Department of Microbiology and ImmunologyRega Institute for Medical ResearchLaboratory of Virology and ChemotherapyLeuven 3000Belgium

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life *** covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic *** antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable *** non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available *** viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

关键词： COVID-19 SARS-CoV-2 Main protease Non-covalent inhibitors Medicinal chemistry strategies

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How mesenchymal stem cells transform into adipocytes:Overview of the current understanding of adipogenic differentiation

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World Journal of Stem Cells 2024年第3期16卷 245-256页

作者： Shan-Shan Liu Xiang Fang Xin Wen Ji-Shan Liu Miribangvl Alip Tian Sun Yuan-Yuan Wang Hong-Wei Chen department of Reumatology and immunology Nanjing Drum Tower HospitalThe Affiliated Hospital of Medical SchoolNanjing UniversityNanjing 210008Jiangsu ProvinceChina department of Emergency Nanjing Drum Tower HospitalThe Affiliated Hospital of Medical SchoolNanjing UniversityNanjing 210008Jiangsu ProvinceChina key laboratory for Biomechanics and Mechanobiology of Ministry of Education School of Biological Science and Medical EngineeringBeihang UniversityBeijing 100191China Anhui key laboratory of infection and immunity Bengbu Medical CollegeBengbu 233000Anhui ProvinceChina

Mesenchymal stem cells(MSCs)are stem/progenitor cells capable of self-renewal and differentiation into osteoblasts,chondrocytes and *** transformation of multipotent MSCs to adipocytes mainly involves two subsequent steps from MSCs to preadipocytes and further preadipocytes into adipocytes,in which the process MSCs are precisely controlled to commit to the adipogenic lineage and then mature into *** studies have shown that the master transcription factors C/enhancer-binding protein alpha and peroxisome proliferation activator receptor gamma play vital roles in ***,the mechanism underlying the adipogenic differentiation of MSCs is not fully ***,the current knowledge of adipogenic differentiation in MSCs is reviewed,focusing on signaling pathways,noncoding RNAs and epigenetic effects on DNA methylation and acetylation during MSC ***,the relationship between maladipogenic differentiation and diseases is briefly *** hope that this review can broaden and deepen our understanding of how MSCs turn into adipocytes.

关键词： Mesenchymal stem cell Adipogenic differentiation Signaling pathway Noncoding RNA Epigenetic regulation

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Individualized anti-thrombotic therapy for acute myocardial infarction complicated with left ventricular thrombus: A case report

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World Journal of Clinical Cases 2024年第4期12卷 835-841页

作者： Yan Song Hua Li Xia Zhang Lei Wang Hong-Yan Xu Zhi-Chao Lu Xiao-Gang Wang Bo Liu department of Clinical Pharmacy Zibo Municipal HospitalZibo 255400Shandong ProvinceChina department of Cardiology Zibo Municipal HospitalZibo 255400Shandong ProvinceChina department of Pharmacy Zibo Municipal HospitalZibo 255400Shandong ProvinceChina department of Imaging Zibo Municipal HospitalZibo 255400Shandong ProvinceChina department of Pulmonary and Critical Care Medicine Department of Clinical MicrobiologyZibo City Key Laboratory of Respiratory Infection and Clinical MicrobiologyZibo City Engineering Technology Research Center of Etiology Molecular DiagnosisZibo Municipal HospitalZibo 255400Shandong ProvinceChina

BACKGROUND Presently,there is no established standard anti-blood clot therapy for patients facing acute myocardial infarction(AMI)complicated by left ventricular thrombus(LVT).While vitamin K antagonists are the preferred choice for oral blood thinning,determining the best course of blood-thinning medication remains *** is unclear if non-vitamin K antagonist oral blood thinners have different effectiveness in treating *** study significantly contributes to the medical *** SUMMARY The blood-thinning treatment of a patient with AMI and LVT was *** blood-thinning therapy included daily enteric-coated aspirin tablets at 0.1 g,daily clopidogrel hydrogen sulfate at 75 mg,and dabigatran etexilate at 110 mg twice *** 15 d,the patient’s LVT did not decrease but instead *** pharmacists comprehensively analyzed the cases from the perspective of the patient’s disease status and drug *** drug regimen was reformulated for the patient,replacing dabigatran etexilate with warfarin,and was administered for six *** clinical pharmacist provided the patient with professional and standardized pharmaceutical *** patient’s condition was discharged after meeting the international normalized ratio value(2-3)*** patient fully complied with the follow-up,and the time in the therapeutic range was 78.57%,with no serious adverse effects during pharmaceutical *** Warfarin proves to be an effective drug for patients with AMI complicated by LVT,and its blood-thinning course lasts for six months.

关键词： Myocardial infarction Left ventricular thrombus Dabigatran etexilate Warfarin Clinical pharmacist Case report

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Targeting PKM2 signaling cascade with salvianic acid A normalizes tumor blood vessels to facilitate chemotherapeutic drug delivery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2077-2096页

作者： Cheng Qian Yueke Zhou Teng Zhang Guanglu Dong Mengyao Song Yu Tang Zhonghong Wei Suyun Yu Qiuhong Shen Wenxing Chen Jaesung P.Choi Juming Yan Chongjin Zhong Li Wan Jia Li Aiyun Wang Yin Lu Yang Zhao Jiangsu key laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China School of Medicine&Holistic Integrative Medicine Nanjing University of Chinese MedicineNanjing 210023China Centre for Inflammation Faculty of ScienceCentenary InstituteSchool of Life SciencesUniversity of Technology SydneySydney NSW 2050Australia Jiangsu key laboratory of immunity and Metabolism Department of Pathogenic Biology and ImmunologyNational Experimental Demonstration Center for Basic Medicine EducationXuzhou Laboratory of Infection and ImmunityXuzhou Medical UniversityXuzhou 221004China department of General Surgery Jiangsu Province Hospital of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjing 210029China Macquarie Medical School Faculty of MedicineHuman Health SciencesMacquarie UniversitySydney NSW 2109Australia

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor ***,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic *** was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to ***,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial *** importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent *** findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.

关键词： Salvianic acid A Tumor vascular normalization PKM2 β-Catenin Claudin-5 Endothelial glycolysis Tight junctions Doxorubicin

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TREM-2 Drives Development of Multiple Sclerosis by Promoting Pathogenic Th17 Polarization

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Neuroscience Bulletin 2024年第1期40卷 17-34页

作者： Siying Qu Shengfeng Hu Huiting Xu Yongjian Wu Siqi Ming Xiaoxia Zhan Cheng Wang Xi Huang Center for infection and immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China The State key laboratory of Respiratory Disease Guangdong Provincial Key Laboratory of Allergy and Clinical ImmunologyThe Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510260China department of laboratory Medicine The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China Division of Nephrology Department of Medicinethe Fifth Affliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

Multiple sclerosis(MS)is a neuroinflammatory demyelinating disease,mediated by pathogenic T helper 17(Th17)***,the therapeutic effect is accompa-nied by the fluctuation of the proportion and function of Th17 cells,which prompted us to find the key regulator of Th17 differentiation in ***,we demonstrated that the triggering receptor expressed on myeloid cells 2(TREM-2),a modulator of pattern recognition receptors on innate immune cells,was highly expressed on pathogenic CD4-positive T lymphocyte(CD4^(+)T)cells in both patients with MS and experimental autoimmune encephalomyelitis(EAE)mouse *** knockout of Trem-2 in CD4^(+)T cells significantly alleviated the disease activity and reduced Th17 cell infiltration,activation,differentiation,and inflammatory cytokine production and secretion in EAE ***,with Trem-2 knockout in vivo experiments and in vitro inhibitor assays,the TREM-2/zeta-chain associated protein kinase 70(ZAP70)/signal transducer and activator of transcription 3(STAT3)signal axis was essential for Th17 activation and differentiation in EAE *** conclusion,TREM-2 is a key regulator of pathogenic Th17 in EAE mice,and this sheds new light on the potential of this therapeutic target for MS.

关键词： Multiple sclerosis Experimental autoimmune encephalomyelitis T helper 17 Triggering receptor expressed on myeloid cells 2

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CD3ε of a pan T cell marker involved in mouse Aspergillus fumigatus keratitis

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International Journal of Ophthalmology(English edition) 2024年第4期17卷 616-624页

作者： Wen-Hao Shi Li-Mei Wang Hai-Jing Yan Shi-Long Liu Xian Yang Xue-JiaoYang Cheng-Ye Che department of Ophthalmology the Affiliated Hospital of Qingdao UniversityQingdao 266000Shandong ProvinceChina Weifang Medical University Weifang 261053Shandong ProvinceChina Eye Hospital of Wenzhou Medical University Wenzhou 325027Zhejiang ProvinceChina department of Medical Engineering the Affiliated Hospital of Qingdao UniversityQingdao 266000Shandong ProvinceChina

AIM:To explore whether CD3ε is involved in the adaptive immunity of Aspergillus fumigatus(***)keratitis in mice and the role of innate and adaptive immunity in ***:Mice models of *** keratitis were established by intra-stromal injection and corneal epithelial *** injections of natamycin,wedelolactone,LOX-1 inhibitor(poly I)or Dectin-1 inhibitor(laminarin)were used to treat mice with *** *** were pretreated by intraperitoneal injection of anti-mouse CD3ε.We observed the corneal infection of mice under the slit lamp microscope and made a clinical *** protein expression of CD3ε and interleukin-10(IL-10)was determined by Western ***:With the disease progresses,the degree of corneal opacity and edema *** the intrastromal injection models,CD3εprotein expression began to increase significantly on the 2^(nd) ***,in the scraping epithelial method models,CD3ε only began to increase on the 3^(rd) *** natamycin treatment,the degree of corneal inflammation in mice was significantly attenuated on the 3^(rd) *** wedelolactone treatment,the severity of keratitis *** the amount of CD3ε protein was also reduced,compared with the control *** inhibiting LOX-1 and Dectin-1,there was no significant difference in CD3ε production compared with the control *** inhibiting CD3ε,corneal ulcer area and clinical score increased,and IL-10 expression was ***:As a pan T cell marker,CD3ε participate in the adaptive immunity of *** keratitis in *** our mice models,the corneas will enter the adaptive immune stage *** regulating IL-10,CD3ε exerts antiinflammatory and repairs effects in the adaptive immune stage.

关键词： CD3ε adaptive immunity Aspergillus fumigatus keratitis interleukin-10

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Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

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Virologica Sinica 2024年第1期39卷 123-133页

作者： Hongbo Guo Dan Liu Kuan Liu Yao Hou Chunyang Li Qiudi Li Xiaohui Ding Monique M.A.Verstegen Jikai Zhang Lingli Wang Yibo Ding Renxian Tang Xiucheng Pan Kuiyang Zheng Luc J.Wvan der Laan Qiuwei Pan Wenshi Wang department of Pathogen Biology and immunology Jiangsu Key Laboratory of Immunity and MetabolismJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhou221004China department of Gastroenterology and Hepatology Erasmus MC-University Medical CenterRotterdamNL-3015 CNthe Netherlands department of Surgery Erasmus MC Transplant InstituteUniversity Medical CenterRotterdam3015CENL-3015 CNthe Netherlands department of Infectious Diseases The Affiliated Hospital of Xuzhou Medical UniversityXuzhou221002China

Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed ***,there are still unmet needs for treating chronic HEV ***,we screened a best-in-class drug repurposing library consisting of 262 drugs/*** screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV *** calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 *** selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV ***,both drugs exhibited a sizeable therapeutic window against *** instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in ***,their anti-HEV mode of action depends on the blockage of pyrimidine ***,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral *** conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV *** on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

关键词： Hepatitis Evirus(HEV) Drug repurposing Vidofludimus calcium Pyrazofurin Pyrimidine biosynthesis

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Targeting a disintegrin and metalloprotease(ADAM)17-CD122 axis enhances CD8^(+)T cell effector differentiation and anti-tumor immunity

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3097-3111页

作者： Lina Sun Anjun Jiao Haiyan Liu Renyi Ding Ning Yuan Biao Yang Cangang Zhang Xiaoxuan Jia Gang Wang Yanhong Su Dan Zhang Lin Shi Chenming Sun Aijun Zhang Lianjun Zhang Baojun Zhang department of Pathogenic Microbiology and immunology School of Basic Medical SciencesXi’an Jiaotong UniversityXi’anShaanxi 710061China Institute of infection and immunity Translational Medicine InstituteXi’an Jiaotong University Health Science CenterXi’anShaanxi 710061China key laboratory of Environment and Genes Related to Diseases Ministry of EducationXi’anShaanxi 710061China Xi’an key laboratory of Immune Related Diseases Xi’anShannxi 710061China Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy Cancer InstituteXuzhou Medical UniversityXuzhouJiangsuChina department of Pediatrics Qilu Hospital of Shandong UniversityJinanChina National key laboratory of immunity and Inflammation Suzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhou 215123 JiangsuChina key laboratory of Synthetic Biology Regulatory Elements Suzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhou 215123 JiangsuChina

CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely *** ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane ***,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T *** and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and ***,ADAM17 regulated CD8^(+)T cells through cleavage of membrane ***17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T ***,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid *** findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.

关键词： immunity stimulation involvement

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Immune regulation of the gut-brain axis and lung-brain axis involved in ischemic stroke

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Neural Regeneration Research 2024年第3期19卷 519-528页

作者： Xiaodi Xie Lei Wang Shanshan Dong ShanChun Ge Ting Zhu Institute of Neuroregeneration&Neurorehabilitation Department of PathophysiologySchool of Basic MedicineQingdao UniversityQingdaoShandong ProvinceChina School of Traditional Chinese Pharmacy China Pharmaceutical UniversityNanjingJiangsu ProvinceChina department of Rehabilitation Medicine The Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina

Local ischemia often causes a series of inflammatory reactions when both brain immune cells and the peripheral immune response are *** the human body,the gut and lung are regarded as the key reactional targets that are initiated by brain ischemic *** microorganisms play an important role in immune regulation and metabolism and affect blood-brain barrier *** addition to the relationship between peripheral organs and central areas and the intestine and lung also interact among each ***,we review the molecular and cellular immune mechanisms involved in the pathways of inflammation across the gut-brain axis and lung-brain *** found that abnormal intestinal flora,the intestinal microenvironment,lung infection,chronic diseases,and mechanical ventilation can worsen the outcome of ischemic *** review also introduces the influence of the brain on the gut and lungs after stroke,highlighting the bidirectional feedback effect among the gut,lungs,and brain.

关键词： enteric glia cells gut microbiota gut-brain axis immune response inflammation ischemic stroke lung-brain axis microglia

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